In:
Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 23 ( 2014-12-01), p. 6045-6058
Abstract:
Purpose: The receptor tyrosine kinase RON is critical in epithelial tumorigenesis and a drug target for cancer therapy. Here, we report the development and therapeutic efficacy of a novel anti-RON antibody Zt/g4–maytansinoid (DM1) conjugates for targeted colorectal cancer (CRC) therapy. Experimental Design: Zt/g4 (IgG1a/κ) was conjugated to DM1 via thioether linkage to form Zt/g4–DM1 with a drug-antibody ratio of 4:1. CRC cell lines expressing different levels of RON were tested in vitro to determine Zt/g4–DM1-induced RON endocytosis, cell-cycle arrest, and cytotoxicity. Efficacy of Zt/g4–DM1 in vivo was evaluated in mouse xenograft CRC tumor model. Results: Zt/g4–DM1 rapidly induced RON endocytosis, arrested cell cycle at G2–M phase, reduced cell viability, and caused massive cell death within 72 hours. In mouse xenograft CRC models, Zt/g4–DM1 at a single dose of 20 mg/kg body weight effectively delayed CRC cell-mediated tumor growth up to 20 days. In a multiple dose-ranging study with a five injection regimen, Zt/g4–DM1 inhibited more than 90% tumor growth at doses of 7, 10, and 15 mg/kg body weight. The minimal dose achieving 50% of tumor inhibition was approximately 5.0 mg/kg. The prepared Zt/g4–DM1 is stable at 37°C for up to 30 days. At 60 mg/kg, Zt/g4–DM1 had a moderate toxicity in vivo with an average of 12% reduction in mouse body weight. Conclusion: Zt/g4–DM1 is highly effective in targeted inhibition of CRC cell-derived tumor growth in mouse xenograft models. This work provides the basis for development of humanized Zt/g4–DM1 for RON-targeted CRC therapy in the future. Clin Cancer Res; 20(23); 6045–58. ©2014 AACR.
Type of Medium:
Online Resource
ISSN:
1078-0432
,
1557-3265
DOI:
10.1158/1078-0432.CCR-14-0898
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2014
detail.hit.zdb_id:
1225457-5
detail.hit.zdb_id:
2036787-9
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